The central objective of this project is to study the role of monokines - immunomodulatory molecules secreted by monocytes and tissue macrophages - as mediators of pulmonary remodeling. These substances (including Macrophage-derived Growth Factor and Tumor Necrosis Factor alpha) represent a family of paracrine hormones released selectively and specifically by macrophages which act locally to modulate the phenotypic expression of non- lymphoid structural cell populations and bring about its pathologic remodeling. The major hypothesis of this project is that pulmonary remodeling results from complex paracrine growth/differentiation factor signals released during lung injury. It is further hypothesized that no single paracrine mediator can be identified as the sole mediator causing pulmonary fibrosis. Thus, a unique feature of these studies will be to examine how monokines in combination affect mesenchymal cell function. The first general goal will be to apply the techniques of biochemistry and molecular immunobiology to characterize the monokines released from human subjects with forms of pulmonary remodeling (sarcoidosis and pulmonary fibrosis), both with respect to their presence and their ultimate effects on targeted structural lung cells. This will be carried out through studies designed to detect their presence through a combination of bioassays and immunoassays, as well as probing for the presence of elevated levels of mRNAs of individual monokines. Parallel studies carried out in animal models of pulmonary injury will provide information about these same monokines over time. A second general goal will be to study how other immune effector cells (T lymphocytes and their lymphokines) modulate macrophage function and monokine release. This will be carried out both in human subjects with pulmonary remodeling, in control human subjects from whom similar lavage cell populations will be obtained, and in animals with well characterized forms of lung injury and remodeling. The third general goal will be to identify a Fibrogenic Factor (a differentiation factor for fibroblasts which induces increased levels of mRNAs for procollagen but does not induce proliferation) in washings from experimental animals and humans with developing pulmonary fibrosis. Close collaboration with other SCOR Projects studying similar patient populations and animal models will provide a unique opportunity to gain new and fundamental insights into these immunologic lung diseases.